Dyrk1A-mediated phosphorylation of RCAN1 promotes the formation of insoluble RCAN1 aggregates

Abstract

The mechanisms underlying aggregate formation in age-related neurodegenerative diseases remain not well understood. Here we investigated whether dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A (Dyrk1A) is involved in the formation of regulator of calcineurin 1 (RCAN1) aggregates. We show that RCAN1 self-associates and forms multimers, and that this process is promoted by the Dyrk1A-mediated phosphorylation of RCAN1 at the Thr(192) residue. Transgenic mice that overexpress the Dyrk1A exhibited lower levels of phospho-Thr(192)-RCAN1 in 10-month-old-group compared to littermate controls, when analyzed with soluble hippocampus lysates. These results suggest that the phosphorylation of RCAN1 by Dyrk1A stimulates the formation of insoluble aggregates upon aging.

Keywords: AD; Aggregation; Aging; Alzheimer's disease; DS; Down syndrome; Dyrk1A; GST; IP; Phosphorylation; RCAN1; TG; WT; dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A; glutathione-S-transferase; immunoprecipitation; pT192-RCAN1; pT212-Tau; phospho-Thr(192)-RCAN1; phospho-Thr(212)-Tau; regulator of calcineurin 1; transgenic; wild-type.